Noviosyloxy coumarin containing compounds



United States Patent Office 3,454,548 Patented July 8, 1969 ABSTRACT OFTHE DISCLOSURE Coumermycin A and coumermycin A (US. Patent 3,201,386)are transformed into valuable intermediates by selectively degrading theparent molecule by the process described herein. For example,coumermycin A is treated with benzyl chloroformate to produce abis-carbobenzoximide derative ('11), said derivative being cleaved byrefluxing in pyridine to produce 3-carbobenzoxamido-4-hydroxy-8-methyl-7-[3-O-(5-methy1 2pyrrolylcarbonyl)noviosyloxy]coumarin (III). Compound III iscatalytically hydrogenated to produce 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl 2 pyrrolylcarbonyl)novio syloxy]coumarin (IV),a valuable intermediate in the preparation of potent new antibioticsubstances, an example of which is 3-benzamido-4-hydroxy-8-methyl-7-[3-O-(5-methyl 2 pyrrolylcarbonyl)noviosyloxy]coumarin (I).

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to chemical compounds useful, for example, in the preparation ofantibacterial agents and, more particularly, to the bis-carbobenzoximideof coumermycin A 3-carbobenzoxamido 4 hydroxy-8- methyl-7-[3-O-(5-methyl2 pyrrolylcarbonyl)noviosyloxy1coumarin and3-amino-4-hydroxy-8-methyl-7-[3- O-(S-methyl 2pyrrolylcarbonyl)noviosyloxy]coumarin, all of which are useful, forexample, in the ultimate preparation of potent antibiotic substances.

Description of the prior art The compounds of the instant invention andtheir usefulness as intermediates in the preparation of thecorresponding 3-benzamido 4 hydroxy-8-methy1-7-[3-O-(5- methyl 2pyrrolylcarbonyl)noviosyloxy1coumarins were heretofore unknown in theart.

SUMMARY OF THE INVENTION The compounds of the present invention,examples of which follow, are prepared by the process which comprisesthe consecutive steps of (a) mixing together a compound having theformula CH3 CH3 CH3 0 0 0 o o HN- 0 CHa NH-C 0- 00m A 9, H Ha H withbenzyl chloroformate to produce a bis-carbobenzoximide (II) having theformula 3 and (b) warming the bis-imide (II) with pyridine to produce a3-carbobenzoxamido compound having the formula 4 major disadvantage ofthe coumermycins however is their poor absorption and resultant lowblood levels. Efforts to correct these deficiencies have resulted in newand novel CH3 N-benzoyl cleavage products of the parent coumermycins, go 0 5 said compounds being antibacterial agents active against yStaphylococcus aureus Smith. (US. patent application I No. 583,984),filed on Nov. 2, 1966 and now abandoned. H360 They are characterized ashaving the formula 6 OH I (7E3 011 10 H36 0 0 O ,=O H3C\/ \[O t NH HaCONH--Ar 1 OH Y I CH: III 011 (3:0 and (c) catalytically hydrogenating(III) to produce a compound having the formula (IV) NH CH3 1 H30 0 O 0wherein R is either hydrogen or methyl, and Ar is a H3o 0 group havingthe formula a H300 NH; R

OH I (I) OH (1:0 R8 in which each of R, R' and R represents hydrogen,fluoro, chloro, bromo, iodo, trifiuoromethyl, trichloro- Iv methyl,amino, N-(lower)alkylamino, N,N-di(lower) alkylamino, nitro, cyano,(lower)alkyl, (lower)alkoxy, hydroxy, carboxamido, N(lower)alkylcarboxamido, DISCLOSURE N,N-di(1ower)alkylcarboxamido,carboxy, carb(lower) This invention relates to derivatives ofcoumermycin alkoxy, acetoxy, mercapto, thioacetoxy or (lower)alkyl- Aand coumermycin A (US. Patent 3,201,386) and to thio; and the nontoxic,pharmaceutically acceptable the processes for their production. Moreparticularly it cationic salts thereof. relates to intermediatesobtained from coumerrnycin A The present disclosure teaches a newprocess for the or A which are valuable in the preparation of antibiotic40 preparation of compounds of Formula I and is more substances.particularly directed to the new intermediate compounds Coumermycin A(R' is methyl) and coumermycin A produced in the practice of the processof the present in- (R' is hydrogen) vention.

CHa CH3 HSC o o o 0 o 0 H307 I o HN--l' 0T CH3 HaCO JNH-E KJ fJ-NH OCH:OH H0 1 O o $11 $11; OH (II-=0 O=C NH HN R RI are efiective ininhibiting the growth of Gram-positive Within the scope of the presentinvention is the process bacteria. Both are nontoxic and exhibit atherapeutic efiect on mice infected with Gram-positive bacteria. A

which comprises the consecutive steps of mixing together a compoundhaving the formula or a cationic salt or tetrahydropyranyl ether thereofwherein R' is hydrogen or methyl, with a benzyl haloformate having theformula /0 Z-CHa-O-C wherein hal is chloro, bromo or iodo, and Z is agroup having the formula E0011 NH-C-O-CHr-Z wherein R and Z are asdescribed above.

Catalytically hydrogenating compound III produces a compound having theformula III H 0 0 0 ma V o HaCO NH:

OH I

wherein R' is hydrogen or methyl.

A preferred embodiment of the present invention comprises the compoundshaving the Formula II, wherein R is methyl and Z is a group having theformula wherein R and R each represent hydrogen, fluoro, chloro, bromo,nitro, cyano, (lower) alkyl, (lower)'alkoxy, or some other equivalentsubstitution.

Another preferred embodiment of the present invention comprises thecompounds having the Formula III, wherein R is methyl and Z is a grouphaving the formula wherein R and R each represent hydrogen, fiuoro,chloro, bromo, nitro, cyano, (lower) alkyl, (lower) alkoxy, or someother equivalent substitution.

A more preferred embodiment of the present invention comprises thecompound having the formula II, wherein R is methyl and Z is phenyl.

Another more preferred embodiment of the present invention comprises thecompound having the Formula III, wherein R is methyl and Z is phenyl.

The most preferred embodiment of the present invention comprises thecompound having the Formula IV, wherein R is methyl, and includes thestable acid addition salts thereof, i.e., hydrochloride, sulfate,phosphate, nitrate, tart-rate, citrate, oxalate, and the like.

The term (lower)alky as used herein means both straight and branchedchain aliphatic hydrocarbon radicals having from one to eight carbonatoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, amyl, hexyl, etc. Where the term (lower)" is used as part ofthe description of another group e.g. (lower)alkoxy, it refers to thealkyl portion of such group' which is therefore as described above inconnection with (lower)alkyl and thus includes such radicals as methoxy,ethoxy, isopropoxy, etc.

Compound IV, where R is either hydrogen or methyl, but preferablymethyl, is an extremely valuable intermediate in the preparation ofcompounds having the Formula I. As was mentioned previously, compoundsof Formula I are most useful as antibacterial agents and, as such, aremost valuable as nutritional supplements in animal feeds, as agents forthe treatment of mastitis in cattle, as therapeutic agents in poultryand animals, including man, in the treatment of infectious diseasescaused by Gram-positive bacteria, especially Staphylococcus aureus andother penicillinase producing bacteria, and sometimes those infectionscaused by Gram-negative bacteria. They are well absorbed and producegood blood levels upon oral or parenteral administration to mammals.

The utility of compound IV, the most preferred embodiment, is in theprocess of preparing compounds of Formula I. One equivalent of compoundof Formula IV is preferably mixed with about 1 to 2 equivalents of anacid halide having the formula Ar-O hal wherein Ar is as defined above,and hal is chloro, bromo or iodo, or with its functional equivalent asan acylating 7 8 agent for a primary amine, in the presence of a protonamine alone or in combination with an inert solvent. accepting solventsystem at about 25 C. for about 24 At a temperature in the range of 20C. to 50 C., hours to produce compounds having the Formula I. butpreferably in the range of C. to about 25 C. to The objectives of thepresent invention have been produce a compound characterized as abis-imide having achieved, by the provision according to the presentinven- 5 the formula CH3 (1H3 H30 0 o 0 0 0 0 CH3 11305 T 0 0 HN o on;H400 NO- C-N OCH 1 V11 /0=(: 0 0 0:0 0 no on, OH 0 I o o I 4H 41.

2 2 /NH l i HN R tion, of the process for the synthesis of compoundshaving Wherein and Z are as described above; and the formula (b) Warmingsaid isolated bis-imide in the presence H 0 E of an anhydrous orwater-wet, proton-accepting solvent 3 0 (organic nucleophrle), usuallyselected from the group consisting of a pyridine, or(lower)trialkylamine such as H400 NH: trimethylamine, triethylamine, butpreferably pyridine, or 031 Am one of these in combination with an inertsolvent, an example of which may be tetrahydrofuran, benzene, tol- CZOuene, xylene, chloroform or ether,

NH At a temperature in the range of 30 C. to the boiling 2/ point of thesolvent system, but preferably in the range of R 70 C. wherein R iseither hydrogen or methyl, which comprises For a period of time of about2 to hours, but preferthe consecutive steps of (a) mixing together acompound 35 ably about 24 hours, having the formula (7H3 (1H3 H30 0 0 oo o 0 cm H36 o H1:I o on:

i l 1 l H300 NH- CNH OCH; I \OH I (H) \l/ y) \l/ HO I 0 OH CH3 on 1 0O=(|} NH HN :l

or a cationic salt or tetrahydropyranyl ether thereof, 50 To produce a3-carbobenzoxamido compound having Wherein R is hydrogen or methyl; witha benzyl halothe formula formate having the formula %0 z-om-o-o CH3 halH30 0 O O Wherein hal is chloro, bromo or iodo, and in which a o 0 Z isa group having the formula H 3 HaCO NHCO CHz-Z R R4 I on (g 0 E Q to Inwhich R and R are alike or different and each represent hydrogen,fluoro, chloro, bromo, nitro, cyano, I: (lower)alky1, (lower) alkoxy, orthe like.

In a homogeneous or heterogeneous system capable of inactivatingprotons, said system comprising an inorganic or organic base selectedfrom the group consisting of an alkali carbonate or bicarbonate, alkaliearth metal carbonate or bicarbonate, a pyridine or a tri(1oWer)alkylamine, alone or in combination with an inert solvent se- Wherein Rand Z are as described above; and lected from the group consisting oftetrahydrofuran, ben- (c) Catalytically hydrogenating the isolated3-carbozene, toluene, xylene, ether, chloroform, etc., butpreferbenzoxamido compound using standard hydrogenation ably in asolvent system comprising a tri(lower)alkyl technique, preferablypalladium or platinum oxide in glacial acetic acid at room temperature,to produce a compound having the formula wherein R is H or methyl.

The process can be conducted under varying conditions, the most criticalbeing the temperature at which the carbobenzoxylation step is performed.

The process, at temperatures in the range of -25 to 25 C., is usuallyperformed by dissolving or suspending coumermycin A or coumermycin A orsoluble salts thereof, i.e., sodium, potassium, or the tetrahydropyranylethers thereof, in a proton accepting solvent (organic nucleophile)usually selected from the group consisting of a (lower) trialkylaminesuch as trimethylamine, triethylamine, or one of these in combinationwith an inert solvent, an example of which may be tetrahydrofuran,benzene, toluene, xylene, chloroform, or ether. The mixture is cooled toabout C. by an ice-water bath. An excess of an unsubstituted orsubstituted benzyl haloformate, preferably in a ratio of two to fourmoles of acylating agent to one mole of coumermycin, is added withvigorous stirring. Stirring is maintained for several hours followingwhich the solution is concentrated to a syrup by evaporation in vacuo attemperatures below 25 C. The material isolated by this technique ischaracterized as a bisimide (II).

Warming the isolated bis-imide (II) in a proton accepting organicsolvent from the group described above at about 40-70 C. overnight, orby refluxing in said solvent for a time of about three hours, results inthe formation of compounds having the Formula III.

The process, at temperatures above 25 C., and up to the boiling point ofthe solvent employed, is usually performed by dissolving or suspendingcoumermycin A or coumermycin A or the soluble salts thereof, or thetetrahydropyranyl ethers thereof, in a proton accepting solvent (organicnucleophile) usually selected from the group consisting of a(lower)trialkylamine such as trimethyla-mine, triethylamine; or one ofthese in combination with an inert solvent, an example of which may betetrahydrofuran, benzene, toluene, xylene, chloroform or ether.

An excess of an unsubstituted or substituted benzyl haloformate,preferably in a ratio of two to four moles of acylating agent to onemole of coumermycin, is added to the mixture with vigorous stirring. Theresultant mixture is slowly warmed to temperatures up to the boilingpoint of the solvent employed for a period of time usually in excess ofthirty minutes but rarely longer than 3 hours, during which timethesolution turns orange to brown in color. The solution is evaporated invacuo to a syrup and poured into vigorously stirred ice-water. Thecrystalline product collected is characterized as material of FormulaII.

As in the procedure as practiced at temperatures below 25 C., theisolated bis-imide (II) was warmed in a proton-accepting organic solventselected from the group described above, preferably in pyridine, atabout 40-70 C. for several hours, to produce product characterized byFormula III in addition to lesser quantities of materials characterizedas having the formulas The resultant mixture obtained from the processby either the high or low temperature procedure is subsequentlyseparated into its component parts, the major one of which is materialof Formula III. Methods satisfactory for said separation includefractional crystallization, chromatography, extraction and other suchequivalents. Because of the generally good solubility of compounds ofFormula III in chloroform, as compared to that of Compounds II, and V,it was relatively simple to extract Compound III from the whole bycontinuous chloroform extraction in a Soxhlet apparatus. Subsequentconcentration of the chloroform extracts, followed by bicarbonatewashings, drying over sodium sulfate, and precipitation usingSkellysolve B produced purified material of the Formula IH.

Purified Product III, possessing an activated amide linkage at the3-position of the coumarin moiety, is readily susceptible tohydrogenolyssis. Catalytic hydrogenation cleaves the nitrogen-carbonylbond of the amide to produce the free amine, Product IV.

'As a general procedure, Product III was dissolved in a suitable solventfor hydrogenation such as acetic acid, a (lower)alkano1, benzene,tetrahydrofuran, etc., but preferably acetic acid, to which was added acatalyst such as palladium, platinum oxide, nickel, or some similarequivalent metal catalyst that would be used in the catalytic reductionof an aldehyde, ketone or unsaturated hydrocarbon. Hydrogen is properlyintroduced into the hydrogenation apparatus and the reduction run athigh or low pressure, but preferably low pressure, in the temperaturerange of about l0 C. to about 50 C., but preferably at about roomtemperature, with adequate agitation until the uptake of hydrogen ceasesor the theoretical amount of hydrogen is absorbed.

The catalyst is immediately removed by filtration in a nitrogenatmosphere and the solution evaporated in vacuo to dryness to yield ayellow-gold product. Recrystallization from ethyl acetate-Skellysolve Bproduces good quality product of Formula IV. The product of Formula IVis susceptible to oxidation and should be stored in a dark containerwith a nitrogen atmosphere. It produces a strong positive Ninhydrin test(intense sky-blue color) and readily reacts with acylating agents suchas acid chlorides to produce compounds of Formula I.

It is a preferred embodiment in the process of preparing compounds ofFormula IV to use coumermycin A or coumermycin A in their free acidicform, or as their 1 l soluble cationic salts, i.e., potassium, sodium,or the like. However, it is also possible to use the tetrahydropyranyl(THP) ethers of coumermycin A or coumermycin A in the process and obtaincomparable results to those of the preferred embodiment.

When the tetrahydropyranyl ethers are used, the process is slightlymodified to include the additional step of cleaving thetetrahydropyranyl group from the molecule. This additional step iscarried out following the recovery of product of Formula II. ThisTHP-bis-imide (II) is usually dissolved or suspended in a(lower)alkanol, or (lower) alkanol-tetrahydrofuran solvent system, alongwith a catalytic amount of p-toluene sulfonic acid, and stirred at roomtemperature for 10-50 hours to effect cleavage of the THP group to yieldthe bis-imide of Formula II. The process is then continued as detailedabove.

PREPARATION OF THE TETRAHYDROPYRANYL ETHERS OF COUMERMYCIN A OR A Purecoumermycin A or coumermycin A is mixed together with excessdihydropyran in the presence of an acid catalyst and an inert solvent toyield mixtures of mono, di, tri and tetra-tetrahydropyranyl etherderivatives of coumermycin A or A respectively.

More specifically, a coumermycin is mixed together with dihydropyran invarious molar proportions, but preferably in a ratio of one mole ofcoumermycin to more than 20 moles of dihydropyran.

The addition of a suitable acid to the coumermycindihydropyran mixtureas a catalyst is essential. The acid employed is usually selected fromthe group consisting of p-toluene-sulfonic acid, hydrochloric acid, etc.

The quantity of the acid employed as the catalyst is usually determinedby the reaction conditions, the bulk of the catalyst and the amount atwhich the optimum yield of product is obtained.

The reaction may be conducted with or without the use of a co-solvent,the co-solvent usually being employed to increase the solubility of thereactants and reduce the viscosity of the mixture. The co-solvent usedis inert and is usually selected from the group consisting oftetrahydrofuran, dioxane, diethyl ether, the dipropyl ethers, thedibutyl ethers, benzene, xylene and toluene.

The reaction is exothermic. Its temperature can be carefully controlledor it can be allowed to seek its own level without substantialdifferences in the end result. The process is usually conducted at atemperature of 100 C., but preferably in the temperature range of 25 to60 C. for a period of time dependent upon the temperature used andultimately upon the completion of reaction and the yields obtained.

As mentioned previously, the process usually results in the formation ofmixtures of mono, di, tri and tetra-substituted tetrahydropyranyl etherderivatives of the coumermycins. The ratio of the components of themixture however, is largely dependent upon the reaction conditions, andmost particularly the method of work-up and purification of same.

When the reaction is conducted at elevated temperatures of 60-80 C. for2 to 4 hours, or at lower temperatures for longer periods of time, undervery anhydrous conditions, followed by purification in the absence ofpolar solvents, there is obtained a product consisting of 80 to 99% pure2',2',4,4-0,0,0,0-tetratetrahydropyranylcoumermycin. The other possibletetrahydropyranylcoumermycins are usually found in the following orderof their relative concentration: 2',2',4-0,0,0-tritetrahydropyranyl2,2-0,0-ditetrahydropyranyl 2'-O-monotetrahydropyranyl coumercycin.

When the reaction is conducted at lower temperatures, or for shorterperiods of time, or under conditions not as anhydrous, the proportion ofthe 2',2',4,4-0,0,0,'O- tetratetrahydropyranylcoumermycin in the mixturedecreases as the proportion of the other tetrahydropyranyl ethersincreases.

It is a fact that the tetrahydropyranyl moiety attached to either orboth 4-O-positions of the coumermycin molecule is quite labile in thepresence of polar solvents. When2',2',4,4-0,0,0,0-tetratetrahydropyranylcoumermycin or2',2',4-0,0,0-tritetrahydropyranylcoumermycin is crystallized orrecrystallized from a hot alcoholic solvent system, the4-O-tetrahydropyranyl ether functions are cleaved to 4-hydroxylfunctions to yield pure 2,2- 0,0-ditetrahydropyranylcoumermycin. The2'-O-tetrahydropyranyl ether functions are generally stable whencrystallization is carried out in the absence of acidic materials.

Resolution of mixtures of the tetrahydropyranyl ether derivatives can beaccomplished by counter-current distribution purification. As apractical matter, the material is suitable as a mixture of di, tri andtetra-tetrahydropyranylcoumermycin, or it can be crystallized from a hotalcoholic solvent system to yield pure2',2'-0,0-ditetrahydropyranylcoumermycin, for use as an intermediate inits ultimate conversion to the N-benzoyl cleavage prodnets of thepresent invention.

The assay used in the examples below is the standard coumermycin A assaywhich is run on Petri plates prepared by using ten ml. of BaltimoreBiological Laboratories (BBL) base agar and a top layer of four ml. ofBBL seed agar innoculated with Staph. aureus ATCC 6538 P. The plates areincubated for 18 hours at 30 C. A standard activity curve forcoumermycin A is determined by using concentrations in the range of 0.07to 1.5 ,lLg./II11.

In the instant invention, use of the word coumermycin, withoutspecifically stating coumermycin A or A shall be taken to mean eitherCoumermycin A or A Di-, tri-, and tetra-tetrahydropyranylcoumermycin Amixture and its resolution Coumermycin A was stirred withtetrahydrofuran (THF) at room temperature until dissolution occurred.Dihydropyran (DHP) was added followed by Amberlyst l5 (H+) resin(containing less than 0.5 %H O). As stirring continued, additional DHPwas added. A gel formed that re-dissolved after one to two hours.Stirring was continued overnight at room temperature during which timethe solution darkened to an orange-brown color.

The Amberlyst resin was removed by filtration and the solutionconcentrated in vacuo to a syrup. Dilution of the syrup with a minimalquantity of methanol yielded a crude solid (-95 of theory). The solidwas dried in vacuo. Thin layer chromatography indicated the solidconsisted of at least three zones (Rf 0.60-0.70) when resolved using9:2l:8 (parts by volume) of methyl acetate: 2-propanol: concentrated NHOH.

A Craig counter-current distribution separation was run on a 15 g.sample of the mixture using /2 volume upper phase to 1 volume lowerphase from a system of 5:1:521 of CCl :CHCl :CH OH:H O over 1001transfers, 97.5% of the solid being recovered in total. The recoveriesby evaporation and subsequent crystallization from the majorconcentrations as determined by Ultra Violet absorption at 345 mg wereas follows: 2,2,4,4-0,0,0,0-tetratetrahydropyranylcoumermycin A Thetetra-substituted tetrahydropyranyl ether of coumermycin A was recoveredfrom tubes 21 through 40 as a pure crystalline solid, 3.68 g., M.P.decomposition above 200 C.

Analysis.-Calcd for C H N O C, 62.27; H, 6.34; N, 4.84. Found: C, 62.03;H, 6.31; N, 4.94.

2,2,4,-0,0,0-tritetrahydropyranylcoumermycin A The tri-substitutedtetrahydropyranyl ether of coumermycin A was recovered from tubes 41-70as a pure crystalline solid, 3.8 g., M.P. decomposition above 200 C.

13 14 Analysis.Cald for C H N O C, 61.71; H, 6.14; The solution wasfiltered to remove the triethylamine N, 5.14. Found: C, 61.65; H, 6.19;N, 5.34. hydrochloride, and then concentrated in vacuo to approximatelyone-tenth its original volume. The light yelloworange solution waspoured into 3000 ml. of Skellysolve-B The di-substituted tetrahydrpyranyl et of 601111161 with vigorous stirring. An immediate precipitateof a mycin 1 Was recovered from tubes 71100 as 3 P light creme-coloredsolid appeared. After stirring for one crystalline Solid, a,decomposition above hour at 25 C. it was filtered, washed with four 100ml. portions of n-hexane, and dried to yield 77.4 g. of semiy for ss vszz s pure bis-carbobenzoximidoeoumermycin A, (as illustrated5-47-F011I1dI C, 10 above). M.P.: Softens at 145-150 C., decomposseswith 2, O monotetrahydmpyranylcoumermycin AP etferyescence at 190200 C.It is probable that this solid,

consisting-mainly of the desired product, was contamin- Themollo-sllbstlmted tetfahydropylanyl ether of ated by small quantities oftriand tetra-substituted carmefmyfiin 1 w covered from tube? as a Pbobenzoxy side products, since one or both of the 4-hycrystalline solid,16 g., M.P. decomposition above 200 C. droxyl f ti f the coumarin i i ofcoumermycin Analysis-"C3160 for 60 65 5 21 60-35; 5'66; A is capable ofbeing carbobenzoxylated as well. It is2,2.,-0,0-ditetrahydropyranylcoumermycin A N, 1 H, noted however, thatthese small quantities of side pro- Qoumermycm 1 was recoverfefliunreacted from tubes ducts do'not interfere with the subsequent steps ofthe 300499, s decomposltlon process and are either eliminated orconverted back to 2,2-0,0-ditetrahydropyranylcoumermycin A desiredproduct as a matter of course as the process is (direct method)practiced. The mfrared spectrum (IR) of the solid product showed a veryweak amide II band near 1530 Coumermycm A (1110.06 g., 1.0 mole) was slll ClIL indicating the presence of little, if any, starting in am1xture of 11.2 liters of dry THF and 11.2 liters of materiaL Staphaureus plate assay 25 to 5.0 meg/mg. dry DHP. p-Toluenesulfomc acldmonohydrate (2.2 g.) 25 EXAMPLE 2 was added and the solution was stirredfor twenty hours at room temperature. The solution was concentrated to/3 Blscarbobenzoxlmlde of coumermycin 1 of the volume in vacuo at lessthan 40 C., filtered and METHOD 2 the filtrate poured into 134 liters ofdry methanol at 0 C. A Solution of of coumermycin 1 in 3 of The productcrystallized upon stirring for minutes at 30 411 tetfahydlofllrantfie'lhylamine Was treated With O-5 C. and was collected by filtration.The filter cake 7.0 g. of benzyl chloroformate by careful addition withwa covered by dry solvent at ll time while washing efficient stirring at25. The reaction mixture was prosame with 10 liters of dry, coldmethanol, followed by 5 tected from the atmosphere and Stirred at for 77liters of petroleum ether. hours. The color changed from a light yellowto deep Recrystallization from hot methanol yielded the descarlet duringthis time. The reaction mixture was concen sired2',2-0,0-ditetrahydr0pyranyl ether. trated to /3 volume in vacuo at 40C. and stored at 4 C. for 16 hours. It was poured into 1000 ml. of icewater DESCRIPTION OF THE PREFERRED with vigorous stirring and acidifiedto pH 1.5 with 250 EMBODIMENTS ml. of 6 N hydrochloric acid. The mixturewas stirred at The following examples will serve to illustrate but not40 0-5 C. for 2 hours and the resulting rose-colored solid to limit thepresent invention. was separated by filtration and washed with five 100ml. -In the Staphylococcus aureus plate assays referred to portions ofwater. Thorough drying in vacuo gave 13.6 g. below, the standard waspure coumermycin A having of amorphous solid that was identical to thatobtained an assigned potency of 1000 mcg./ mg. in the procedure ofExample I.

EXAMPLE 1 ZQ 3 Bis-carbobenzoximide of coumermycin ABis-carbobenzoximide of coumermycin A METHOD 3 METHOD 1 v A solution of15.0 g. of tetrahydropyranylcoumermycin CH3 CH3 H30 0 o o o o 0 CH3 H=oo HN- 0 CHa H300 J -oUo- OCH: OH 0=c 0 ii (5:0 H0 no A) on. 1 onMonosodium coumermycin A g., 0.053 mole) was A in 350 ml. 6:1 ofTHF-triethylamine was treated with dissolved in 1250 ml. oftetrahydrofuran (THF) with 7.0 g. of benzyl chloroformate. The reactionmixture was slight warming on a steam bath. After allowing the deepprotected from the atmosphere and stirred at 25 C. for

yellow-gold solution to cool to 25 C., 44.6 ml. of triethyl- 30 hours.The mixture was concentrated in vacuo at 40 amine (6 equivalents) wascarefully added with vigorous C. to 50 ml. of dark orange-brown syrup.It was poured stirring. The mixture immediately started to gel, althoughinto 1.00 liter of water with vigorous stirring, and the pH rapidstirring kept the gel mobile. was adjusted to 1.5 with 200 ml. of 6 Nhydrochloric Five equivalents (36 ml.) of benzylchloroformate, diacidwhile cooling in ice at 0-5 C. The resulting suspenluted to 250 ml.volume with THF, was added dropwise sion was stirred at 0 C. for 2.0hours and the amorphous to the vigorously stirred gel-solution at 25 C.over a 30 solid was filtered olf. The total crude product, afterthorminute period. ough drying, was dissolved in a mixture of 90 ml. of

After one hour, the gel disappeared and the presence acetone, 370 ml. ofmethanol, and 1.8 ml. of 2,2-dimethof triethylamine hydrochlorideprecipitate was noted. The oxypropane, and 930 mg. of p-toluenesulfonicacid monostirring of the yellow solution was continued at 25 C. forhydrate was added. The clear red solution was stirred at an additional24 hours. 25 for 25 hours and then evaporated to dryness at 40 EXAMPLE 43-carbobenzoximido-4-hydroxy-8-methyl-7- 3-O- 5-methyl-Z-pyrrolylcarbonyl noviosyloxy] coumarin Seventy-five g. of thebis-carbobenzoximide of coumermycin A obtained in Example I wasdissolved in 1200 ml. of pyridine at 25 C. to make a lightorange-colored solution. It was warmed to 50-55 C. for at least 24 hoursduring which time it was stirred.

The resultant orange-brown solution was concentrated in vacuo to aboutone-fifth its original volume and was poured into 3000 ml. of ice waterwith vigorous stirring; The pH was adjusted to pH 1-2 with 6 Nhydrochloric acid, then stirred for an additional hour.

The suspension was filtered to yield 57.9 g. of light cream-tan coloredsolids which were dried in vacuo to constant weight.

The carbobenzoxamido derivative is quite chloroformsoluble while theundesired side products are not. The whole solids (50. g.) were placedin a Soxhlet extraction apparatus and continuously extracted until thematerials extracted from the whole became negligible. Evaporation of thechloroform extracts produced approximately 15 g. of chloroform solublematerials. This residue was redissolved in a small portion of chloroformand extracted with aqueous sodium bicarbonate to remove any acidicimpurities. The chloroform solution was dried over anhydrous sodiumsulfate and fractionally precipitated from solution by the addition ofincreasing amounts of Skellysolve-B (petroleum solvent, B.P. 60-68 C.,essentially n-hexane) to yield a pure fraction, 4.5 g., of materialidentified as 3-carbobenzoximido-4-hydroxy-8- methyl 7 [3 O(5-methyl-2-pyrrolylcarbonyl)noviosyloxy1coumarin as a white,crystalline solid, M.P.: softens at 110 C., gelling at 125 C., meltswith effervescence at 155-160 C.

The infrared (IR) and nuclear magnetic resonance (NMR) spectra wereconsistent with the structure of the title compound. Staph. aureus plateassay 90 to 110 meg/mg.

Analysis.-Calcd for C H O N C, 61.73; H, 5.51; N, 4.50. Found: C, 61.14;H, 5.65; N, 4.83.

EXAMPLE 5 3 -amino-4-hydroxy-'8 -rnethyl7- [3 -O-(S-methyl-Z-pyrrolylcarbonyl) noviosyloxy]coumarin (Platinum oxidecatalyst) 3 carbobenzoxamido-4-hydroxy-8methyl-7-[3-0-(5-methyl-Z-pyrrolylcarbonyl)noviosyloxy] coumarin (1.8 g., 2.90 mmoles),obtained from Example 4, was dissolved in ml. of glacial acetic acid toproduce a pale yellow solution. To this solution was added 500 mg. ofplatinum oxide catalyst and the resultant solution-suspension treatedwith hydrogen in a Parr hydrogenation apparatus at an initial pressureof 52.5 1b./in. The reduction was run for 24 hours at room temperaturewith agitation. The total uptake of hydrogen was 15.7 lb./in.

The catalyst was removed by filtration over a filter-aid pad under anitrogen atmosphere, and the solution was immediately evaporated invacuo. Twenty ml. of acetone was added to the residue and it was againevaporated to dryness in vacuo. The procedure was repeated 4 more times.The resultant residue was dried in vacuo over sodium hydroxide .to yield1.0 g. of a light yellow-gold solid, M.P. 196-200" C. IR and NMRanalysis of this solid was consistent with the structure of the titlecompound, 3 amino-4-hydroxy-8-methyl-7[3-0-5-methyl-2-pyrrolylcarbonyl)noviosyloxy]coumarin. The material is recrystallizedand used for the preparation of compounds having the Formula I. Theproduct gives a sky-blue Ninhydrin test. It is sensitive to oxidation,particularly when in solution.

Analysis.-Calcd for C H O N C, 59.01; H, 5.79; N, 5.74. Found: C, 58.39;H, 6.02; N, 5.70.

Analysis.-Calcd for C H O N /2H O: C, 57.94; H, 5.88; N, 5.63.

EXAMPLE 6 3-amino-4 hydroxy-8-methyl-7-[3-0- (5-methyl-2-pyrrolylcarbonyl )-noviosyloxy] coumarin. (Palladium catalyst) 3carbobenzoxamido 4 hydIoxy-methyl-7-[3-O-5-methyl-Z-pyrrolylcarbonyl)noviosyloxy]coumarin (2.0 g., 3.22 mmoles),obtained from Example 4, was dissolved in 200 ml. of glacial aceticacid. To this solution was added 500 mg. of 30% palladium ondiatomaceous earth, and the hydrogenation was conducted on a Parrhydrogenation apparatus as in Example 5.

The reduction was run for 24 hours at 25 C. and the hydrogen uptake was8.4 lbs/in. The product was worked up in an identical manner to thatused in Example 5 to yield about 1.4 g. of solid material that wasidentical in every respect with that obtained in Example 5.

EXAMPLE 7 3-benzamido-4-hydroxy-8-anethyl-7-[3-O-5-methyl-2-pyrrolylcarbonyl novio syloxy] coumarin 0 O O O 3 amino 4hydroxy-8-methy1-7-[3-0-(5-methy1-2-pyrrolycarbonyl)noviosyloxylcoumarin (250 mg, 0.51 mmole), obtained fromExample 5, was dissolved in 10 ml. of pyridine.

To this solution was added benzoic anhydride (139 mg., 0.613 mmole) withvigrous stirring at 25 C. The reaction was stirred at room temperaturefor a total of 70 hours under a N atmosphere and then poured into 150ml. of ice water containing 20 ml. of 6 N hydrochloric acid. The mixturewas stirred for one hour and the precipitate colleced by vacuumfiltration to yield 253 mg. of a light peach-colored solid that wasidentified as 3- benzamido 4 hydroxy 8 methyl-7-[3-O-(5-rnethyl-2- HaCO17 pyrrolylcarbonyl)noviosyloxy]coumarin, M.P.: tans and softens 190 C.,browns beginning at 210 0., finally decomposes vigorously at 230-235 C.(turns black). Staph. aureus assay 44 gJ-mg.

Analysis.-Calcd for C H O N C, 62.83; H, 5.45; N, 4.73. Found: C, 63.49;H, 5.7 8; N, 4.43.

EXAMPLE 8 3 carbobenzoxamido 4 hydroxy-8-methyl-7-[3-0-(5- methyl 2pyrrolylcarbonyl)noviosyloxy]coumarin. (Alternate-direct procedure)Monosodium coumermycin A (60 g., 0.053 mole) is dissolved in 1500 ml. of6:1 THF-triethylamine to which solution is added dropwise and with rapidstirring five equivalents (36 ml.) of benzyl chloroformate. Thetemperature of the solution is gradually raised to reflux temperaturesfor several hours. One-half the solvent is removed in vacuo and replacedby an equal amount of pyridine. The solution is warmed overnight. Thebulk of the solvent evaporated in vacuo and the resultant syrup pouredinto 3000 ml. of rapidly stirred ice-water. The pH of the mixture isadjusted to pH 1-2 with 6 N hydrochloric acid, stirred for an additionalhour and the tan precipitate collected by filtration. The precipitate iswashed well with water, air dried, dried in vacuo and the wholesubsequently extracted by chloroform in a Soxhlet extraction apparatusto yield product identical in every way to the 3 carbobenzoxamido 4hydroxy-8-methyl-7[3-O- (S-methyl 2 pyrrolycarbonyl)noviosyloxy1coumarinobtained in Example 4.

EXAMPLE 9 Bis-carbobenzoximide of coumermycin A Substitution in theprocedure of Examples 1, 2 or 3 for the coumermycin A or coumermycin A-tetrahydropyranyl ethers used therein of coumermycin A or coumerycin A-tetrahydropyranyl ether produces the biscarbobenzoximide of coumermycinA EXAMPLE 10 3-carbobenzoxamido-4-hydroxy-8-methyl-7-[3-0-(2-pyrrolylcarbonyl)noviosyloxy]coumarin Substitution in the procedure ofExample 4 for the biscarbobenzoximide of coumermycin A used therein ofthe bis-carbobenzoximide of coumermycin A produces 3- carbobenzoxamido 4hydroxy 8 methyl-7-[3-O-(2- pyrrolylcarbonyl)noviosyloxy]coumarin.

EXAMPLE 11 3-amino-4-hydroxy-8 methyl-7-[3-O-(2pyrrolylcarbonyl)noviosyloxy]coumarin Substitution in the procedure ofExample or 6 for the 3 carbobenzoxamido 4 hydroxy-8-methyl-7-[3-O-(S-methyl 2 pyrrolylcarbonyl)noviosyloxy]coumarin used therein of3-carbobenzoxamido-4-hydroxy-8-methyl 7-[3-0-(2pyrrolylcarbonyl)noviosyloxy]coumarin produces 3amino-4-hydrox-y-8-methy1-7-[3-O-(2-pyrrolylcarbonyl)noviosyloxy]coumarin.

EXAMPLE 12 Bis-4nitrocarbobenzoximide of coumermycin A Substitution inthe procedure of Examples 1, 2 or 3 for the benzyl chloroformate usedtherein of 4-nitrobenzyl cbloroformate produces thebis-4-nitrocarbobenzoximide of coumermycin A EXAMPLE 13 3- (4-nitrocarbobenzoxamido -4-hydroxy-8-methyl-7- [3 O- (S-methyl-Z-pyrrolylc arbonylnoviosyloxy/coumarin Substitution in the procedure of Example 4 for thebiscarbobenzoximide of coumermycin A used therein of thebis-4-nitrocarbobenzoximide of coumermycin A pro- 18 duces3-(4-nitrocarbobenzoxamido)-4-hydroxy-8-methyl- 7-[3-0-(5 methyl 2pyrrolylcarbonyl)noviosyloxy] coumarin.

EXAMPLE 14 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-rnethyl-2-pyrrolylcarbonyl noviosyloxy] coumarin Substitution in the procedure ofExamples 5 or 6 for the 3-carbobenzoxamido 4 hydroxy-8-methyl-7-[3-O-(S-methyl 2 pyrrolylcarbonyl)noviosyloxy]coumarin used therein of3-(4-nitrocarbobenzoxamido)-4-hydroxy- 8-methyl-7-[3-O-(5-methyl 2pyrrolylcarbonyl)noviosyloxy]coumarin produces3-amino-4-hydroxy-8-methyl- 7-[3-0-(5 methyl 2pyrrolylcarbonyl)noviosyloxy] coumarin.

EXAMPLE 153-amino4-hydroxy-8-methyl-7-[3-0-(S-methyl-Z-pyrrolylcarbonyDnoviosyloxy]coumarin hydrochloride Tetrahydropyranyl ether of3-amino-4-hydroxy-8-methyl- 7-[3-O-(5-methyl 2pyrrolylcarbonyl)-noviosyloxy] coumarin.

A solution .of 15.0 g. of tetrahydropyranylcoumermycin A in 350 m1. offreshly-distilled pyridine was treated with 7.0 g. of benzylchloroformate. The reaction mixture was protected from the atmosphereand stirred at 25 C. for 30 hours. The mixture was concentrated in vacuoat 40 C. to 50 ml. of dark orange-brown syrup. It was poured into 1.00liter of water with vigorous stirring. The resulting tetrahydropyranylbis-imide suspension is stirred at 0 C. for 2.0 hours and the amorphoussolid filtered ofl. The total crude product is dissolved in 1200 ml. ofpyridine at 25 C. to make a light orange-colored solution. It is warmedto 50-55 C. for 24 hours during which time it is stirred.

The resultant orange-brown solution is concentrated in vacuo to aboutone-fifth its original volume and is poured into 3000 ml. of ice waterwith vigorous stirring.

The suspension is filtered to yield light cream-tan colored solids whichare dried in vacuo to constant weight.

The tetrahydropyranyl-carbobenzoxamido derivative is quite chloroformsoluble while the undesired side products are not. Thewhole solids areplaced in a Soxhlet extraction apparatus and continuously extracteduntil the materials extracted from the whole became negligible.Evaporation of the chloroform extracts produces a solid residue. Thisresidue is redissolved in a small portion of chloroform and extractedwith 5% aqueous sodium bicarbonate to remove any acidic impurities. Thechloroform solution is dried over anhydrous sodium sulfate andfractionally precipitated from solution by the addition of increasingamounts of Skellysolve-B (petroleum solvent, B.P. 60-68" (3.,essentially n-hexane) to yield a purified fraction of thetetrahydropyranyl ether of 3- carbobenzoximido-4-hydroxy8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl noviosyloxy] coumarin.

The tetrahydropyranyl ether of the S-carbobenzoxamido4-hydroxy-8-methyl-7-[3-O-(S-methyl-Z-pyrrolylcarbonyl)noviosyloxy]coumarinis dissolved in 150 ml. of glacial acetic acid or benzene to produce apale yellow solution. To this solution is added 500 mg. of platinumoxide catalyst and the resultant solution-suspension is treated withhydrogen in a Parr hydrogenation apparatus at an initial pressure of52.5 lb./in. The reduction is run for about 24 hours at room temperaturewith agitation.

The catalyst is removed by filtration over a filter-aid pad under anitrogen atmosphere, and the solution is immediately evaporated invacuo. Twenty ml. of acetone is added to the residue and it is againevaporated to dryness in vacuo. The procedure is repeated several times.The resultant residue is dried in vacuo over sodium hydroxide to yieldthe tetrahydropyranyl ether of 3-amino- 4 hydroxy 8methyl-7-[3-O-(S-methyl-Z-pyrrolylcarbonyl novio syloxy] coumarin.

EXAMPLE 17 3-amino 4-hydroxy-methyl-7-[3-O-(5-methyl 2pyrrolylcanbonyl)noviosyloxy]coumarin via the tetrahydropyranyl etherThe tetrahydropyranyl ether of 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl 2 pyrrolylcarbonyl)noviosyloxy]coumarin obtainedin Example 16 is dissolved in a mixture of acetone and methanol whichcontains a small quantity of 2,2-dimethoxypropane and p-toluenesulfonicacid. The clear yellow-orange solution is stirred at room temperaturefor about 20 hours and then evaporated in vacuo to yield an oilyresidue. The residue is dissolved in chloroform, washed with 5% NaHCOsolution, dried over Na SO and taken to dryness in vacuo.Recrystallization from acetone-Skellysolve B produces crystalline titlecompound.

While in the foregoing specification various embodiments of thisinvention have been set forth in specific detail and elaborated for thepurpose of illustration, it will be apparent to those skilled in the artthat this invention is susceptible to other embodiments and that many ofthe details can be varied widely without departing from the basicconcept and the spirit and scope of the invention.

We claim:

1. A compound having the formula OHa wherein R is either hydrogen ormethyl, R is either hydrogen or a radical having the formula 20 in whichR and R are alike or different and each represent hydrogen, fluoro,chloro, brorno, cyano, (lower)- alkyl, (lower)alkoxy or nitro, and R iseither hydrogen or and when R is hydrogen, the stable acid additionsalts thereof.

2. A compound of claim 1 having the formula H30 0 H@o T /O o H3CO NHR OR0 OH ('J=o wherein R' is either hydrogen or methyl, R is either hydrogenor a radical having the formula in which R and R are alike or differentand each represent hydrogen or nitro, and R is either hydrogen or andwhen R is hydrogen, the stable acid addition salts thereof. 3. Acompound of claim 1 having the formula CH3 H o H:O\ O\ O\ /0 0 H300 NHR3 OR I OH wherein R is either hydrogen or a radical having the formula an O 0 @H.

in which R represents hydrogen or nitro, and R is either hydrogen or andwhen R is hydrogen, the stable acid addition salts thereof.

wherein Y R is either hydrogen or methyl, and Z is a group having theformula 4. A compound of claim 1 having the formula CH: H80 0 0 5 mo =omoo NH:

NH i 7. A compound of claim 6 having the formula CH3 CH8 H 0 o HaC- H300\J: OH

and the stable, acid addition salts thereof.

5. A compound of claim 1 having the formula wherein H 0 Z is a grouphavmg the formula H30 0 0 H300 NH-JE-O-om-Q-m wherein R is eitherhydrogen or nitro.

in which R is hydrogen or nitro.

CH3 OH! H 0 11:0 /0\ o\ /O -o EN- 0 0\ /O 0\ moo N-C i C-N OH H I H HO O6 0 E B II o: .1

)IE HN 6. A compound having the formula CH3 CH3 H30 0 o 0 O o 0 CH5 H3O0 HN-| o CH3 H400 NCKJ-O-N K OCH;

a g H 0B 0: t 0 R 0 2 O HO (5 CH: =0

l H NH h g HN in which R and R are alike or difi'erent and eachrepresent hydrogen, fluoro, chloro, bromo, cyano, (lower)alkyl, (lower)alkoxy or nitro, and R is either hydrogen or 8. The process whichcomprises the conseoutive steps of (a) mixing together as compoundhaving the formula OH: CH3

OCHa

23 24 or a cationic salt or tetrahydropyranyl ether thereof,catalytically hydrogenating the isolated 3-carbowherein R is hydrogen ormethyl, benzoxamido compound with a benzyl haloformate having theformula to produce a compound having the formula ZCHzO( J-hal whereinha! is chloro, bromo or iodo, and Z is a group having the formula T l 0H300 \JNH! 0R5 1 Hi (I) OH in which R and R are alike or different andeach 5 represent hydrogen, fluoro, chloro, bromo, nitro, cyano,(lower)alkyl, or (lower)alkoxy NH to produce a compound characterized asa bisimide having the formula CH3 CH3 H 0 o o o 0 CH3 Hwj Q o HN I OTICK, H CO NOw-c-Nl/ OCH 3 Q; g n 3 HO 1 CH3 I OH O 6 0 o =0 (IJ I O=C 1E /NH 2 z HN\ R wherein R and Z are as described above; and R is eitherhydrogen or /0 wherein R and R is as described above; and the stableacid addition salts thereof.

I 9. The process of claim 8 which comprises the consecu- 4O tive stepsof d (a) mixing together a compound having the formula an (b) warmingsaid isolated bis-imide in the presence of CH3 (1H5 H30 0 o o o o 0 CH3H3O o HN-I o CH3 H300 N-CUO-N 00H;

\ H u n H OH 0 5 o 1 HO I OH H3 011 C=O a proton-accepting solvent or acationic salt or tetrahydropyranyl ether thereof,

to produce a 3-carbobenzoxamido compound havwherein R is hydrogen ormethyl,

ing the formula with a benzyl haloformate having the formula 0 CH y lz-om-ohal H30 0 o o H3O 0 wherein hal 1s chloro or bromo, and Z is agroup 5 having the formula H 00 NH(i00Hi-z 0R6 I CH in which R and R arealike or different and each represent hydrogen, fluoro, chloro, bromo,nitro, cyano, (lower)alkyl or (lower)alkoxy,

to produce a compound characterized as a biswherein R R and Z are asdescribed above; and imide having the formula lo t 25 6.. CH3 7 CH8 H30o o o 0 0 1140 o HN--l- 0 on; H400 N-ow-m- OCH: 4 ii 4 OR o: A =0 R 0 A0 HO 4 Ha I OH 4 0 0 4 I :0 2TH] 6H1 NH i i HN wherein R and Z are asdescribed above; and

R is either hydrogen or wherein R and R is as described above; and the ostable acid addition salts thereof. 10. The process of claim 8 whichcomprises the coni NH and Y (b) warming said isolated bis-imide in thepresence of a proton accepting solvent selected from the groupconsisting of a pyridine, or (lower)trialkylamine to produce a3-carbobenzoxamido compound having the formula 45 H30 0 O O EBCV 0 0H400 NHt J0CH4-z OR 0 11 4 E wherein R R and Z are as described above;and (c) catalytically hydrogenating the isolated 3-carbobenzoxamidocompound using a metal catalyst to produce a compound having the formulasecutive stepsof (a) mixing together a compound having the formula or acationic salt or tetrahydropyranyl ether thereof wherein R is hydrogenor methyl with a benzyl with a benzyl chloroformate having the formulawherein Z is a group having the formula furan, benzene, toluene, xylene,ether and chloroform,

at a temperature in the range of 20 C. to

to produce a compound characterized as a bis-imide having the formulaCH3 H5 0R6 0 0:0 R 0 H0 1 3 5 \OH 5 zo H (IJH 0:0 2 I 2 l /NH 2 z HN\ tR R! wherein R and Z are as described above; hydrogen is absorbed toproduce a compound and R is either hydrogen or having the formula (3H3H30 0 o 0 0 H30 0 H300 NH:

OR (I) H and 0:0 (b) warming said isolated bis-imide in the presence ofN a proton accepting solvent selected from the group H consisting of apyridine or (lower)trialkylamine, I alone or in combination with aninert solvent se- R lected from the group consisting of tetrahydrofuran,wherein R and R is described as above; and the benzene, toluene, xylene,ether and chloroform, stable addition salts thereof.

at a temperature in the range of 30 C. to the 11. The process of claim 8which comprises the conboiling point of the solvent system, secutivesteps of for a period of time of about two to fifty hours, (a) mixingtogether a compound having the formula (3H3 CH3 HaC 0 O O CH: H10 o HN-o CHa H (I; I] H OH I (5 O HO I OH Ha OH 0:0 0:0 k NH EN CH3 CH3 toproduce a 3-carbobenzoxamido compound havor a cationic salt with abenzyl chloroforrnate having ing the formula the formula H30 0 0 CH! 0Z-CH o h 01 B50 O H CO NH-l-O-CHr-Z wherein Z is a group having theformula NE in which R is hydrogen or nitro, I 5 in a homogeneous systemcapable of inactivating R protons, said system comprising an organicbase wherein R R and Z are as described above; and selected from thegroup consisting of tri(lower) (c) catalytically hydrogenating theisolated, purified alkylamines, alone or in combination with an3-carbobenzoxamido compound using a metal cata inert solvent selectedfrom the group consisting lyst, of tetrahydrofuran, benzene, toluene,xylene,

hydrogen at a pressure in the range of about ether, chloroform,

1 lb./in. to 300 lb./in. at a temperature in the range of about 5 C. ata temperature of about 0 C. to about 50 C. to about 35 C. in a suitablesolvent for hydrogenation, with agitato produce a compound characterizedas a bistion, until at least the theoretical amount of imide having theformula OH I CH: O

OCHa

hydrogen at a pressure in the range of about 25 lb./in. to about lb./in.

at a temperature of about 15 C. to about 35 C. in glacial acetic acid,with agitation, until the theoretical amount of hydrogen is absorbed toproduce a compound having the formula CH3 H C y\/\ 9 O HaCOU NH:

OH 2) $11 J =o and the stable, acid addition salts thereof.

References Cited UNITED STATES PATENTS 3,201,386 8/1965 Ka-waguchi etal. 3,268,511 8/1966 Kiss et al 260-234 45 LEWIS GOTTS, PrimaryExaminer.

JOHNNIE R. BROWN, Assistant Examiner.

wherein Z is as described above; and (c) catalytically 'hydrogenatingthe isolated, purified 3-carbobenzoxamido compound using platinum oxideor palladium oxide catalyst,

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,454,548 July 8 1969 John G. Keil at al.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 20, lines 46 to 58, that portion of the formula reading A O l LOC==O should read H CH C 3 Column 22, line 46 "as" should read o lines 47to 65, that portion of the formula reading:

HN should read H Column 23, lines 19 to 33, that portion of the formulareading:

HSC H c 3 SC O f H 0 0 r H CO 0H H CO 0R5 0 should read i will.

FILM- w ll Column 26 line 41 "wherein R is hydrogen or methyl with abenzyl" should read wherein R is hydrogen or methyl Signed and sealedthis 24th day of March 1970 (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

